Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent progress in the definition of molecules involved in immune regulation has led to the discovery of a number of type I membrane glycoproteins with a distinctive, cysteine-rich, repetitive domain structure within their extracellular regions. Because the prototype members of this family are receptors for cytokines (tumor necrosis factor [TNF] and nerve growth factor [NGF]), it was expected that the ligands for the other receptors would possess cytokine-like activities. This prediction has been fulfilled by the cloning of cDNA encoding a series of type II membrane glycoproteins, with homology to TNF, that bind to, and signal through, their cognate receptors. While the biological role of some of these ligand-receptor pairs remains obscure, at least two members of the family, CD40 and Fas, have proven their importance. The human X-linked immunodeficiency, hyper IgM syndrome, is the result of mutations in the CD40 ligand gene, and the Fas and Fas ligand genes are mutated in two mouse strains, lpr and gld, that develop autoimmune disease. These findings, together with other evidence, point to key roles of CD40/CD40 ligand interactions in immune activation, particularly in T-dependent B cell responses, and of Fas/Fas ligand in apoptosis and peripheral tolerance. These molecules, as well as the other ligands of the family, share the property of costimulation of T cell proliferation and are all expressed by activated T cells. More detailed analysis of the expression patterns of ligands and receptors on lymphocyte subpopulations will be necessary to define their different roles in immune activation and suppression.
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PMID:A family of ligands for the TNF receptor superfamily. 752 88

The Src family protein-tyrosine kinase Lyn associates physically with the BCR and has been suggested to play an important role in BCR-mediated signaling. Studies with lyn-/- mice showed that the number of B cells decreased by half in their peripheral tissues. In addition, these B cells do not respond normally to a number of stimuli, including BCR cross-linking and CD40 ligand. Induction of tyrosine phosphorylation on a variety of cellular proteins, such as Vav, Cbl, and HS1, upon BCR cross-linking was also abolished in these B cells. Despite the impaired BCR-mediated signaling, concentrations of IgM and IgA in sera were remarkably elevated, and production of autoantibodies was detected in lyn-/- mice. Histological study showed splenomegaly and enlargement of lymph nodes that became evident with age in the mutant mice. The spleen contained significant number of plasma cells as well as unusual lymphoblast-like cells carrying Mac1 antigen and cytoplasmic IgM. These cells spontaneously secreted a large amount of IgM in vitro. Finally, significant number of lyn-/- mice show glomerulonephritis, an indication of autoimmune disease. From these data, we conclude that Lyn plays a role in signal transduction for not only clonal expansion and terminal differentiation of peripheral B cells but also elimination of autoreactive B cells.
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PMID:Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice. 758 45

The specificity of T cell help for B cell activation and differentiation is maintained by the brief expression on the T cell surface, following T cell receptor-mediated triggering, of CD40 ligand (CD40L). Interaction of T helper (Th) cell CD40L with B cell CD40 induces B cell activation, cell surface expression of activation antigens, proliferation, and initiation of immunoglobulin isotype switch. We predicted that in patients with systemic lupus erythematosus (SLE), in whom Th cell-dependent production of autoantibodies results in immune complex-mediated tissue damage, CD40L expression might be augmented, prolonged, or abnormally regulated. Baseline expression of CD40L was increased in some SLE patients studied, when compared with control subjects. While Th cells from normal subjects (n = 14) and rheumatic disease control patients (n = 9) showed maximal expression of CD40L, after in vitro activation with phorbol myristate acetate (PMA) and ionomycin, at 6 h of culture with diminished levels observed at 24 and 48 h, Th cells from SLE patients (n = 19) maintained high level cell surface expression of CD40L through 24 and 48 h of culture. The prolonged expression of CD40L was functionally significant, as 24 h-activated SLE T cells, when cocultured with target B cells, induced greater B cell surface CD80 (B7-1) expression than did 24 h-activated normal T cells. These results document impaired regulation of CD40L expression in SLE T cells and identify an important potential target for therapy in this systemic autoimmune disease.
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PMID:Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. 869 75

The molecular mechanisms of the primary immunodeficiencies have been further explored and provide insights into the regulation of the immune response and its role in autoimmune disease, infection, and malignancy. The critical role of CD40-CD40 ligand-mediated effects in T cell-dependent B cell activation, shown through the study of patients with common variable immunodeficiency and hyper IgM syndrome, suggests a potential narrow target for immunomodulatory therapy. A mouse model for chronic granulomatous disease has been developed and promises to be a source of future information. Optimal cost-effective therapy for primary immunodeficiencies continues to be defined, with the results of a large series of patients treated with subcutaneous immunoglobulin infusions reported. Further experience with polyethylene glycol adenosine deaminase and interleukin-2 conjugates is discussed.
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PMID:Immunodeficient states and associated rheumatic manifestations. 886 40

Mechanisms of B cell apoptosis are critical in reducing aberrant B cell proliferations such as those that arise in autoimmune disease and in B cell malignancies. The physiologic interaction of CD4+ helper T cells and B lymphocytes has been extensively studied over the past two decades. Although CD4+ T cells are considered primarily to offer positive costimulatory signals for B cell differentiation into active immunoglobulin-secreting cells, recent studies have shown that CD4+ T cells are crucial in downregulating the humoral immune response. In the course of cognate interaction between CD40 ligand (CD40L)-bearing CD4+ T cells and CD40-expressing germinal center B cells, CD40 ligation results in augmented Fas expression at the B cell surface. Like CD40L, Fas ligand is expressed on activated CD4+ Th1 cells and when bound to Fas receptor on the B cell surface, initiates an apoptotic signal in that cell. Thus, CD4+ T cells limit the growth of autologous germinal center B cells by first inducing Fas expression and then instigating a death signal via Fas ligand. In this work, we will consider these observations about CD4+ T-cell-induced, Fas-mediated B cell death in the context of other factors that affect apoptosis in B cells, normal and malignant.
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PMID:Fas expression and apoptosis in human B cells. 890 79

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system postulated to be a cell-mediated autoimmune disease in which interferon gamma (IFN-gamma) plays an important role. There is increased IFN-gamma secretion in MS, and IFN-gamma administration induces exacerbations of disease. We found that interleukin 12 (IL-12) was responsible for raised IFN-gamma secretion in MS as anti-IL-12 antibodies reversed raised anti-CD3-induced IFN-gamma in MS patients to normal levels. Furthermore, we found a marked increase in T cell receptor-mediated IL-12 secretion in progressive MS patients vs. controls (24.8 +/- 7.7 pg/ml vs. 1.5 +/- 1.0 pg/ml, P = 0.003) and vs. relapsing-remitting patients (3.7 +/- 1.4 pg/ml, P < 0.05). Investigation of the cellular basis for raised IL-12 demonstrated that T cells from MS patients induced IL-12 secretion from non-T cells, and that T cells from MS patients could even drive non-T cells from normal subjects to produce increased IL-12. Anti-CD40 ligand antibody completely blocked IL-12 secretion induced by activated T cells, and we found increased CD40 ligand expression by activated CD4+ T cells in MS patients vs. controls. The CD40 ligand-dependent Th1-type immune activation was observed in the progressive but not in the relapsing-remitting from of MS, suggesting a link to disease pathogenesis and progression and providing a basis for immune intervention in the disease.
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PMID:Increased interleukin 12 production in progressive multiple sclerosis: induction by activated CD4+ T cells via CD40 ligand. 901 30

Male BXSB mice, unlike female BXSB, develop a severe early onset lupus-like disease that has been linked to an intrinsic B cell defect. In investigating this B cell defect the present study showed that male, but not female, BXSB contained a higher percentage of large, activated splenic B cells that were more responsive to anti-CD40 mAb-induced proliferation. The hyperactivity of the large B cells from the male mice was also observed in the absence of anti-CD40 mAb or any other stimuli. In examining the mechanism of the B cell hyperactivity, it was found that 20% of unstimulated large B cells from male mice, unlike large B cells from female mice, expressed CD40 ligand (CD40L), a molecule normally expressed on activated CD4+ cells. The percentage of large B cells from the male BXSB that expressed CD40L was increased to 43% by stimulation with LPS. A functional role for CD40L expression on B cells was confirmed by showing that CD40-Ig blocked the spontaneous proliferation of the large B cells from male mice. In addition, the stimulatory capacity of the large B cells from the male mice was demonstrated by their ability to induce DNA synthesis in small B cells in a CD40L-dependent manner. These results demonstrated that large B cells from male BXSB expressed functionally active CD40L. It is likely that the B cell CD40L expression and increased susceptibility to CD40 signaling due to an intrinsic B cell hyperactivity promotes autoimmune disease in BXSB mice.
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PMID:CD40 ligand expressed on B cells in the BXSB mouse model of systemic lupus erythematosus. 937 59

The CD40/CD40L (CD40 ligand) axis regulates several interactions between T cells and B cells. Blocking of CD40 engagement by CD40L inhibits Ig class switch by B cells as well as diminishes T cell response to an immunizing Ag. For these reasons, disruption of CD40/CD40L interactions by anti-CD40L administration or by genetic disruption of CD40L has ameliorated a variety of autoimmune conditions. More recent findings suggest that a direct signal can be transmitted to T cells via their expressed CD40L, which can costimulate proliferation with CD3 or promote germinal center formation. It is therefore possible that treatment with anti-CD40L Ab might produce a different outcome than observed in genetically CD40L-deficient mice. In this regard, we observe that in contrast to the genetic deletion of CD40L in MRL-lpr mice, which diminishes autoimmune disease but has little effect on adenopathy, administration of anti-CD40L to MRL-lpr mice accelerates both of these parameters. This difference appears to result from anti-CD40L actively delivering a signal that inhibits T cell apoptosis in lpr mice. This was confirmed by in vitro studies demonstrating that CD40L cross-linking on lpr thymocytes inhibited apoptosis and surface TCR down-modulation induced by CD3 ligation.
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PMID:Anti-CD40L accelerates renal disease and adenopathy in MRL-lpr mice in parallel with decreased thymocyte apoptosis. 967 Sep 49

The pharmacokinetics and pharmacodynamics (PK/PD) of chimeric (Ch5c8) and humanized (Hu5c8) 5c8, a monoclonal antibody that binds CD154 (CD40 ligand), thus blocking the interaction between CD40 and CD154, were investigated in cynomolgus monkeys. Single-dose groups (n = 3 animals per dose) received saline, 0.2, 1, 5 or 20 mg/kg i.v. doses of Hu5c8. The repeat-dose groups (n = 4 animals) received 0 or 5 mg/kg i.v. doses of Ch5c8 or Hu5c8 on days 1, 2, 3, 5, 7 and 9. The single-dose PK parameters showed dose proportionality, with a terminal half-life of 300 h, a volume of distribution at steady state of 73 ml/kg and clearance of 0.2 ml.h-1.kg-1. The repeat-dose regimen produced a longer terminal half-life (500 h) and lower clearance (0.13 ml.h-1.kg-1) than in the single-dose groups. The antibody titer to tetanus toxoid (ATT) challenge served as the immunodynamic marker. The primary ATT response consisted of a latent phase of approximately 10 days, during which the immune system was processing antigen but not yet producing antibody, a rise to an antibody maximum titer at approximately 18 days and a decline toward baseline by approximately 40 days in controls. The 5c8 produced a log(dose)-proportional reduction in the area under the curve of ATT. An indirect PK/PD model based on the kinetics of tetanus toxoid exposure and inhibition of ATT production in relation to 5c8 concentrations was developed. A median inhibitory concentration of 0.84 microg/ml and a efficacy of 0.84 reflected marked inhibition of ATT response by 5c8. The model provides quantitation of reduced ATT responses after 5c8 and was applicable to primary and secondary immune responses and to both single-dose and multiple-dose treatments. The monoclonal antibody 5c8 blocks the CD40 and CD154 interaction, producing consistent and substantive reduction in antibody formation after administration of tetanus toxoid, which can be characterized with PK/PD modeling. It is anticipated that 5c8 may have utility in the treatment of antibody-mediated autoimmune disease.
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PMID:Pharmacokinetics/dynamics of 5c8, a monoclonal antibody to CD154 (CD40 ligand) suppression of an immune response in monkeys. 969 51

The interactions of CD28-B7 and CD40-CD40 ligand (CD40L) pathways in T cell costimulation and autoimmune disease are incompletely understood. We sought to address this issue by investigation of the genesis of acetylcholine receptor (AChR)-induced antibody-mediated experimental autoimmune myasthenia gravis (EAMG) in CD28- and CD40L-deficient mice (CD28-/-, CD40L-/-). Compared to wild-type mice, the CD28-/- mice became less susceptible, and CD40L-/- mice were completely resistant to EAMG induction. Analysis of T helper functions, reflected by cytokine responses, revealed a switch to a Th1 profile in CD28-/- mice. Consistently, levels of serum AChR-specific antibodies of the IgG1 isotype were decreased in CD28-/- mice. In the CD40L-/- mice, both Th1 and Th2 cytokine responses were diminished, and T cell-dependent AChR-reactive B cell responses were more severely impaired than in the CD28-/- mice. Thus, CD28 and CD40L are differentially required for induction of EAMG.
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PMID:Differential requirements for CD28 and CD40 ligand in the induction of experimental autoimmune myasthenia gravis. 984 1


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